1. Field of the Invention
The present invention relates generally to the fields of medical physics and drug delivery. More specifically, the present invention relates to methods and devices for controlling the delivery of pharmaceutical compounds through the skin and other tissue interfaces.
2. Description of the Related Art
Drug delivery is a critical aspect of medical treatment. In many cases, correct administration of drugs is critical to the overall efficacy of its action, and thus, patient compliance becomes a significant factor in therapy. For this reason, the physician should carefully monitor drug delivery.
Drug delivery is particularly important in acute care settings. Patients must often endure long hospital stays post-surgery or other treatment to ensure that drugs are administered properly. In this case, and many others, a patient must remain in close contact with the physician during the course of treatment. This compliance issue, and the cost of long-term hospital stays, has resulted in significant research and development of devices capable of delivering controlled, continuous and sustainable release of therapeutics.
Skin has a very thin layer of dead cells, called the stratum corneum, which acts as an impermeable layer to matter on either side of the layer. The stratum corneum is what primarily provides the skin""s barrier function. If the stratum corneum is removed or somehow altered, then materials within the body can more easily diffuse out to the surface of the skin, and materials outside the body can more easily diffuse into the skin. Alternatively, compounds referred to as permeation enhancers (e.g. alcohol) or drug carriers (e.g. liposomes) can be used, with some success, to penetrate the stratum corneum. In any case, the barrier function of the skin presents a very significant problem to pharmaceutical manufacturers who may be interested in topical administration of drugs, or in transcutaneous collection of bodily fluids.
Mucosa, which is the moist lining of many tubular structures and cavities (e.g. nasal sinuses and mouth), consists in part of an epithelial surface layer. This surface layer, which consists of sheets of cells with strong intercellular bonds, in single or multiple layers, and that have a non-keratinized or keratinized epithelium. On the basolateral side of the epithelium is a thin layer of collagen, proteoglycans and glucoproteins called the basal lamina, and which serves to bind the epithelial layer to the adjacent cells or matrix. The mucosa acts as a barrier to prevent the significant absorption of topically applied substances, as well as the desorption of biomolecules and substances from within the body. The degree to which mucosa acts as a barrier, and the exact nature of the materials to which the mucosa is impermeable or permeable, depends on the anatomical location. For example, the epithelium of the bladder is 10,000 times less xe2x80x9cleakyxe2x80x9d to ions than the intestinal epithelium.
The mucosa is substantially different from skin in many ways. For example, mucosa does not have a stratum corneum. Despite this difference, permeation of compounds across mucosa is limited and somewhat selective. The most recent model of the permeability of mucosa is that the adjacent cells in the epithelium are tightly bound by occluding junctions, which inhibit most small molecules from diffusing through the mucosa, while allowing effusion of mucoid proteins. The molecular structure of the epithelium consists of strands of proteins that link together between the cells, as well as focal protein structures such as desmosomes. The permeation characteristics of mucosa are not fully understood, but it is conceivable that the selective permeability of the mucosa may depend on this epithelial layer, which may or may not be keratinized, as well as the basal lamina. While it has been shown that removal or alteration of the stratum corneum of skin can lead to an increase in skin permeability, there is no corresponding layer on the mucosa to modify. Thus, it is not obvious that electromagnetic energy irradiation will cause a modification of the permeability of mucosa.
Various methods have been used for facilitating the delivery of compounds across the skin and other membranes. Iontophoresis uses an electric current to increase the permeation rate of charged molecules. Iontophoresis however is dependent on charge density of the molecule, and furthermore, has been known to cause burning in patients. Use of ultrasound has also been tested whereby application of ultrasonic energy to the skin results in a transient alteration of the skin, resulting in increased permeability to substances. Electromagnetic energy produced by lasers may be used to ablate stratum corneum in order to make the skin more permeable to pharmaceutical substances (U.S. Pat. No. 4,775,361), and, impulse transients generated by lasers or by mechanical means may be used to make alterations in epithelial layers that result in improved permeation of compounds (U.S. Pat. No. 5,614,502).
There are many therapeutic and diagnostic procedures that would benefit from a transmucosal or transendothelial route of administration or collection. For example, local anesthetics, such as lidocaine, are delivered to a region prior to a medical treatment. Such a local administration of lidocaine could be efficacious at providing anesthesia, but would minimize any side-effects and eliminate the need for a needle. Local administration of an antineoplastic drug into the bladder wall could greatly minimize the time required for a patient to hold a drug in the bladder during chemotherapy.
Electrosurgery, which is a method whereby tissue coagulation and/or dissection can be effected. In electrosurgery, radiofrequency (RF) current is applied to tissue applied by an (active) electrode. In a bipolar system, the current is passed through tissue between two electrodes on the same surgical instrument, such as a forceps. In a monopolar system, a return-path (ground) electrode is affixed in intimate electrical contact, with some part of the patient. Because of the importance of the ground electrode providing the lowest impedance conductive path for the electrical current, protection circuits monitoring the contact of the ground with the patient are often employed whereupon an increase in ground electrode-skin impedance results in the instrument shutting down. Factors involved in electrosurgical system include treatment electrode shape, electrode position (contact or non-contact) with respect to the tissue surface, frequency and modulation of the RF, power of the RF and time for which it is applied to the tissue surface, peak-to-peak voltage of the radiofrequency, and tissue type. In typical electrosurgical systems, radiofrequency frequencies of 300 kHz to 4 MHz are used since nerve and muscle stimulation cease at frequencies beyond 100 kHz. For example, all else being equal, decreasing electrode size translates into increased current density in the tissue proximal to the electrode and so a more invasive tissue effect, such as dissection, as compared to coagulation. Similarly, all else being equal, if the electrode is held close to the tissue, but not in contact, then the area of RF-tissue interaction is small (as compared to the area when the electrode is in contact with the tissue), and so the effect on the tissue is more invasive. By changing the waveform of the applied RF from a continuous sinusoid to packets of higher peak voltage. sinusoids separated by dead time (i.e. a duty cycle of, say, 6%), then the tissue effect (all else being equal) can be changed from dissection to coagulation. Holding all else equal, increasing the voltage of the waveform increases the invasiveness of the tissue effect. Of course, the longer the tissue is exposed to the radiofrequency, the greater the tissue effect. Finally, different tissues respond to radiofrequency differently because of their different electrical conductive properties, concentration of current. carrying ions, and different thermal properties.
The prior art is deficient in the lack of effective means of controlling the rate of pharmaceutical delivery or biomolecule collection by utilizing electromagnetic energy, wherein controlled electromagnetic energy driven systems are integrated into patches and other delivery devices. The present invention fulfills this long-standing need and desire in the art.
The present invention provides a microprocessor which may be controlled, and may be communicated with, over analog and digital telecommunication links, including the Internet. Specifically, the present invention describes microprocessor-controlled transdermal patches that use electromagnetic energy to enhance the uptake of a pharmaceutical formulation in contact with a membrane or skin. The devices could also be used to increase the diffusion of the substances, as well as endogenous biomolecules, out of tissue. The electromagnetic energy inherent to the inventions described herein is often referred to as microwave (MW) and radiofrequency (RF).
The application of the present invention is not limited to delivery across oral mucosa or skin. Other anatomical structures including, for example, vaginal, uterine, intestinal, buccal, tongue, nasopharyngeal, anal, and bladder walls, as well as vascular, lymphatic and urethral vessels are also applicable. Importantly, the present invention can be used to breach compromised or intact stratum corneum and the tissue layers underneath in order to deliver compounds across skin, and with many drugs, through intact skin. Furthermore, this method may be used to control systems that drive substances across non-biological membranes and films.
In one embodiment of the present invention, there is provided a method for controlling delivery of a pharmaceutical compound in a subject, comprising the steps of: irradiating the subject with electromagnetic energy; and applying the pharmaceutical compound to the subject, wherein the compound is contained in a patch. Preferably, the electromagnetic energy is selected from the group consisting of radiofrequency, microwave and light. The patch may be implanted in the subject or topically positioned in relation to the subject, and controlled locally or remotely by an external controller, such as a microprocessor.
In another embodiment of the present invention, there is provided a system for controlling the rate of pharmaceutical delivery or biomolecule collection in a subject, comprising: a means to generate electromagnetic energy; a means to deliver the electromagnetic energy to the subject; and a means to administer the pharmaceutical to or collect the biomolecule from the subject, wherein the pharmaceutical is contained in a patch controlled locally or remotely by an external controller. Preferably, the electromagnetic energy is selected from the group consisting of radiofrequency, microwave and light, and means to generate electromagnetic energy include lasers and ultrasound transducers. Preferably, the controller is a microprocessor, powered by a battery, a solar cell, an electrochemical generator, a thermal energy generator, or an piezeoelectric generator. The patch may be implanted in the subject or topically positioned in relation to the subject, and furthermore, the patch may be made of material selected from the group consisting of a dressing material, a gel, a viscous material, and an adhesive material.
In a preferred embodiment, the patch contains one or more reservoirs separated by a rupturable membrane(s). In the case of multiple reservoir-containing patch, lyophilized crystal portion of an unstable pharmaceutical compound is stored in one reservoir, while liquid portion of the compound is stored in another reservoir. An example of such compound is prostaglandin E1.
The above disclosed system can further comprise an electrode, wherein the electrode is in contact with both the patch and controller, and transmits an electrical current or electromagnetic radiant energy. Or the same system can further comprises a computer monitor connected to the Internet, wherein a signal is sent over the Internet, through the computer monitor, and into the patch.
In still another embodiment of the present invention, there is provided a drug delivery or biomolecule collection patch, wherein the patch is electronically monitored by global positioning system.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.